Steatosis or lipid accumulation in non-adipocytes occurs in about 25 percent of cadaveric livers used for transplantation. Although usually asymptomatic, hepatic steatosis is a significant risk factor for postoperative liver failure, as fatty livers are much more sensitive to ischemia-reperfusion injury than normal "lean" livers. Thus, fatty livers are often considered to be "marginally acceptable" for transplantation. Our long-term goal is to develop a metabolic pre-conditioning regimen, which reduces hepatic lipid storage and increases the liver's ability to withstand ischemia-reperfusion injury. We hypothesize that metabolic pre-conditioning will reduce the risk of postoperative liver dysfunction to a level similar to that observed in non-steatotic livers.Our specific aims are: (1) To characterize the metabolic and vascular homeostatic mechanisms in steatotic livers; (2) To intervene via metabolic conditioning techniques to reduce the sensitivity of hepatocytes and perfused livers to ischemia-reperfusion injury; (3) To optimize metabolic conditioning techniques for livers used in pre-clinical models of liver surgery. In the short-term, the proposed studies could (1) provide the rationale basis for increasing the liver donor pool size, as severely steatotic livers are usually discarded; (2) improve the outcome of patients which receive liver transplants with mild to moderate steatosis; and (3) provide new ways to prevent or limit hepatic fibrosis, as hepatic steatosis often precedes fibrosis in degenerative liver diseases. The long-term outcomes of this project are (1) scientific and technology bases to develop defatting methods for other organ systems affected by steatosis, such as pancreatic beta cells and cardiomyocytes in obese individuals; and (2) warm perfusion techniques with the potential to significantly increase organ storage time beyond the limits of current cold storage techniques.